Myelogenous Leukemia, Chronic
Conditions
Keywords
leukemia, bone marrow, leukemia symptoms, lukemia, cml, complete blood count, lymphocyte, blood cancer, leukocytes, chronic leukemia, bone marrow biopsy, leukemia research, leukemia cells, bone marrow disease, chronic myeloid leukemia, blood cancer symptoms, white blood cell diseases, chronic myelogenous leukemia, leukemia treatment, leukemia facts, leucemia, facts about leukemia, myelogenous leukemia, newly diagnosed CML, newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP)
Brief summary
In this study, the efficacy and safety of two nilotinib doses, 300 mg twice daily and 400 mg twice daily, were compared with imatinib 400 mg once daily in newly diagnosed patients with Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia in the chronic phase (CML-CP). An extension protocol was included in this study design to allow patients who did not show sufficient response to their assigned treatments the opportunity to receive imatinib 400 mg BID (option available until protocol amendment 7) or nilotinib 400 mg BID, using an abbreviated safety and efficacy assessment schedule.
Detailed description
Primary objectives of this study: * Compared the efficacy (major molecular response (MMR) rate at 12 months) of nilotinib at 400 mg bid with that of imatinib 400 mg qd in newly diagnosed, previously untreated Ph+ CML-CP patients. * Compared the efficacy (MMR rate at 12 months) of nilotinib at 300 mg bid with that of imatinib 400 mg qd in newly diagnosed, previously untreated Ph+ CML-CP patients. The Primary objectives of Extension Phase of the study: \- Characterized the safety and tolerability profile of nilotinib 400 mg BID after failure of imatinib or insufficiently responded to nilotinib 300 mg BID therapy and the safety and tolerability profile of imatinib therapy after failure of nilotinib therapy. The study was designed to determine whether the treatment of newly diagnosed, previously untreated Ph+ CML-CP patients with either nilotinib 300 mg bid or 400 mg bid demonstrated improved efficacy compared to imatinib 400 mg qd. The primary efficacy endpoint was the rate of MMR defined as the proportion of patients who achieved ≥ 3 log reduction in BCR-ABL transcripts compared to either the standardized Baseline established in the IRIS trial (International Randomized Interferon versus STI571) (Cortes et al 2005) or to the BCR-ABL ratio ≤ 0.1% by International Scale, as detected by real-time quantitative polymerase chain reaction (RQ-PCR) at 12 months. The key secondary endpoint was to compare the rate of durable MMR between nilotinib 300 mg bid with that of imatinib, and of nilotinib 400 mg bid with that of imatinib at 24 months. This report presents the final results of efficacy and safety at the LPLV (21-Aug-2019). The main data analysis was done at the time when all patients completed 12 cycles of treatment (or discontinued earlier). There were two primary comparisons at this time point: the MMR rate of nilotinib 400 mg versus the MMR rate of imatinib 400 mg, and the MMR rate of the nilotinib 300 mg versus the MMR rate of the imatinib 400 mg. Comparisons were done sequentially, i.e. the MMR rate of nilotinib 400 mg versus the MMR rate of imatinib 400 mg was to be compared first; if it was significant at 5% level, the MMR rate of the nilotinib 300 mg versus the MMR rate of the imatinib 400 mg was to be compared. The study had a 90% power to detect a 15% difference between the nilotinib 400 mg arm versus imatinib 400 mg arm assuming that the MMR rate of imatinib is 40% and the MMR rate of nilotinib is 55%. The study also had a 90% power to detect a 15% difference between the nilotinib 300 mg and the imatinib 400 mg arms, if the comparison between the nilotinib 400 mg and the imatinib 400 mg was significant. The second main data analysis was done at the time when all patients completed 24 cycles of treatment (or discontinued earlier). There were two key comparisons at this time point: the rate of durable MMR at 24 months of the nilotinib 400 mg versus the imatinib 400 mg, and the rate of durable MMR at 24 months of the nilotinib 300 mg versus the imatinib 400 mg. In order to control the overall type I error rate at or below 5%, only when the corresponding comparison on the primary efficacy endpoint(s) was (were) significant, the key secondary comparison(s) of the respective nilotinib doses (400 mg bid and/or 300 mg bid) versus imatinib 400 mg qd were tested at two-sided 5% significance level. Patients participating after demonstrating suboptimal response/treatment failure to their assigned study treatment in the core study were offered the option to continue in the extension study and to receive imatinib 400 mg bid (option available only until protocol amendment 7) or nilotinib therapy at a dose of 400 mg bid.
Interventions
DRUGnilotinib
Nilotinib was supplied as 50 mg, 150 mg and 200 mg hard gelatin capsules and administered orally at 300 mg BID (twice a day) or 400 mg BID (twice a day)depending on the randomized dose.
DRUGimatinib
Imatinib was supplied as 100 mg and 400 mg tablets and administered orally at 400 mg QD (once a day).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: * Chronic myelogenous leukemia in chronic phase patients within the first 6 months of diagnosis. * Diagnosis of chronic myelogenous leukemia in chronic phase with confirmation of Philadelphia chromosome of (9:22) translocations Key
Exclusion criteria
* Previously documented T315I mutation * Treatment with a tyrosine kinase inhibitor prior to study entry is not allowed except for no more than 2 weeks in duration of imatinib * Any medical treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide * Impaired cardiac function. * Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection). * Use of therapeutic coumarin derivatives (i.e., warfarin, acenocoumarol, phenprocoumon) * Currently receiving treatment with any medications that have the potential to prolong the QT interval.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation | Baseline, 12 months | MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months. |
| Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | 12 months | MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms | 12 months | MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months based on 12-month cut-off interim data. |
| Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months | MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 6 months and beyond up to 120 months based on final data. |
| Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months | Molecular response of \<=0.01% is defined as BCR-ABL ratio (%) on IS \<= 0.01% (corresponds to \>=4 log reduction of BCR-ABL transcripts from standardized baseline value) |
| Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months | This is the molecular response of \<=0.0032% is defined as BCR-ABL ratio (%) on IS \<= 0.0032% (corresponds to \>=4.5 log reduction of BCR-ABL transcripts from standardized baseline value) |
| Time to First MMR | up to 84 months | Time to MMR is defined as time from date of randomization to the date of the first documented MMR in nilotinib treatment arms, compared to imatinib in adult patients with Ph+ CML in CP. |
| Duration of MMR | approx. 11 years | Duration of MMR for patients with MMR is defined as the time between date of MMR and the earliest of the following: loss of MMR, CML-related death or progression to AP/BC during study treatment The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported. |
| Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | up to 84 months | Time to BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% is defined as: date of first BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% - date of randomization +1. |
| Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | approx. 11 years | It is defined as the time from the date of first documented BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% to the earliest of the following: Loss of BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032%, respectively, CML-related death or progression to AP/BC during study treatment. The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported. |
| Rate of Hematologic Response | 12 months, 24 months, Overall on Core study (approx. 11 years) | Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes \< 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver). |
| Time to Complete Cytogenic Response (CCyR) | 24 months | Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR |
| Duration of CCyR | up to 72 months | Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR. |
| Progression-free Survival (PFS) | approx. 11 years | Progression-free survival is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring in the core or extension study, or during the follow-up period after discontinuation of core or extension study |
| Event-free Survival (EFS) | approx. 11 years | Event-free survival is defined as the time from the date of randomization to the date of first occurrence of any of the following: death due to any cause (if death is the primary reason for discontinuation), progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR |
| Rates of Durable MMR at 24 Months Between All 3 Arms | 24 months | Durable MMR at 24 months is defined as having MMR both at 12 months and at 24 months, and with no documented loss of MMR between these 12 month and 24 month time points. |
| Actual Dose-intensity | approx. 11 years | Actual dose intensity is defined as total dose over time on treatment |
| Time to Progression to AP/BC | approx. 11 years | Time to progression to AP/BC is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of CML related death. |
| Pharmacokinetics: Cmax | any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration | Cmax is defined as the maximum serum concentration after dose |
| Pharmacokinetics: Cmin | any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration | Cmin is defined as the minimum serum concentration after dose |
| Pharmacokinetics: Tmax | any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration | Tmax is defined as the sampling time when maximum measured serum concentration occurs |
| Pharmacokinetics: AUC0-last | any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration | AUC0-last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method |
| Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | Overall for Extension study for approx. 10 years | Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes \< 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver). |
| Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | Overall for Extension study for approx. 10 years | Rate of CCyR is defined as the percentage of participants in complete cytogenetic response (CCyR). CcyR is defined as 0% of Ph+ metaphases in the bone marrow. |
| Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | Overall for Extension study for approx. 10 years | Rate of MMR is defined as the percentage pf participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) |
| Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | Overall for Extension study for approx. 10 years | Molecular response of \<=0.01% is defined as BCR-ABL ratio (%) on IS \<= 0.01% (corresponds to \>=4 log reduction of BCR-ABL transcripts from standardized baseline value) |
| Rate of ≥ 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | Overall for Extension study for approx. 10 years | Molecular response of \<=0.0032% is defined as BCR-ABL ratio (%) on IS \<= 0.0032% (corresponds to \>=4.5 log reduction of BCR-ABL transcripts from standardized baseline value) |
| Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension) | Overall for Extension study for approx. 10 years | This is the percentage of patients with any emergent mutation on extension treatment. The mutation comprised of T315T, less sensitive to nilotinib, unknown and sensitive to nilotinib. |
| Overall Survival (OS) | approx. 11 years | OS is defined as the time from the date of randomization to the date death. Up to 10 calendar years of follow up from the date when the last patient randomized received the first dose of study drug in all active treatment arms of adult patients with Ph+ CML CP. |
| Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | 12, 24, 36, 48, 60, 72 months (M) | CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Patients with no CCyR as the best response by any specific time point, all missing cytogenetic evaluations by that time point or Ph- at baseline are combined as Nocomplete cytogenetic response. |
Countries
Argentina, Austria, Belgium, Brazil, Canada, Colombia, Czechia, Denmark, Egypt, Finland, France, Germany, Hong Kong, Hungary, Italy, Japan, Malaysia, Mexico, Netherlands, Norway, Poland, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States, Venezuela
Participant flow
Recruitment details
The study over-enrolled, and 846 patients (283 in the imatinib 400 mg arm, 282 in the nilotinib 300 mg arm and 281 in the nilotinib 400 mg arm) were randomized. DP = disease progression, SOR/TF = Suboptimal response or treatment failure
Pre-assignment details
Randomization was planned for a total of 771 patients.
Participants by arm
| Arm | Count |
|---|---|
| Imatinib 400 mg QD Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated | 283 |
| Nilotinb 300 mg BID Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated. | 282 |
| Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated. | 281 |
| Total | 846 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Treatment Phase | Abnormal Laboratory Values | 3 | 9 | 9 |
| Core Treatment Phase | Abnormal Test Procedures | 1 | 0 | 1 |
| Core Treatment Phase | Administrative problems | 14 | 14 | 12 |
| Core Treatment Phase | Adverse Event | 43 | 53 | 89 |
| Core Treatment Phase | Condition no longer requires study drug | 0 | 1 | 0 |
| Core Treatment Phase | Death | 3 | 9 | 3 |
| Core Treatment Phase | Disc. Core/Entered Ext. - DP progression | 2 | 0 | 0 |
| Core Treatment Phase | Disc. Core/Entered Ext.- SOR/TF | 46 | 26 | 3 |
| Core Treatment Phase | Disease Progression | 10 | 2 | 4 |
| Core Treatment Phase | Lost to Follow-up | 6 | 6 | 3 |
| Core Treatment Phase | Protocol Violation | 6 | 15 | 11 |
| Core Treatment Phase | Sub optimal response or treat. failure | 19 | 11 | 13 |
| Core Treatment Phase | Withdrawal by Subject | 31 | 29 | 34 |
| Extension Phase | Adverse Event | 9 | 5 | 1 |
| Extension Phase | Death | 1 | 0 | 0 |
| Extension Phase | Disease progression | 2 | 0 | 0 |
| Extension Phase | Lost to Follow-up | 2 | 0 | 0 |
| Extension Phase | Protocol Violation | 2 | 2 | 0 |
| Extension Phase | Unsatisfactory therapeutic effect | 8 | 6 | 0 |
| Extension Phase | Withdrawal by Subject | 3 | 1 | 0 |
Baseline characteristics
| Characteristic | Imatinib 400 mg QD | Nilotinb 300 mg BID | Nilotinib 400 mg BID | Total |
|---|---|---|---|---|
| Age, Customized >= 35 - <45 years | 67 Participants | 50 Participants | 59 Participants | 176 Participants |
| Age, Customized <35 years | 63 Participants | 67 Participants | 65 Participants | 195 Participants |
| Age, Customized >=45 - <55 years | 63 Participants | 72 Participants | 65 Participants | 200 Participants |
| Age, Customized >=55 - < 65 years | 55 Participants | 57 Participants | 65 Participants | 177 Participants |
| Age, Customized >=65 years | 35 Participants | 36 Participants | 27 Participants | 98 Participants |
| Race/Ethnicity, Customized Asian | 71 Participants | 76 Participants | 66 Participants | 213 Participants |
| Race/Ethnicity, Customized Black | 7 Participants | 12 Participants | 11 Participants | 30 Participants |
| Race/Ethnicity, Customized Caucasian | 187 Participants | 170 Participants | 185 Participants | 542 Participants |
| Race/Ethnicity, Customized Native American | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 17 Participants | 24 Participants | 17 Participants | 58 Participants |
| Sex: Female, Male Female | 125 Participants | 124 Participants | 106 Participants | 355 Participants |
| Sex: Female, Male Male | 158 Participants | 158 Participants | 175 Participants | 491 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 280 | 10 / 279 | 5 / 277 | 19 / 836 |
| other Total, other adverse events | 275 / 280 | 276 / 279 | 272 / 277 | 823 / 836 |
| serious Total, serious adverse events | 96 / 280 | 112 / 279 | 126 / 277 | 334 / 836 |
Outcome results
Primary
Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation
MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
Time frame: Baseline, 12 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation | 22.3 Percentage of participants |
| Nilotinb 300 mg BID | Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation | 44.3 Percentage of participants |
| Nilotinib 400 mg BID | Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation | 42.7 Percentage of participants |
p-value: <0.000195% CI: [14.5, 29.6]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [12.9, 28]Cochran-Mantel-Haenszel
Primary
Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation
MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
Time frame: 12 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg QD | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = Interm. | 22.8 Percentage of participants |
| Imatinib 400 mg QD | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = Low | 26.0 Percentage of participants |
| Imatinib 400 mg QD | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = High | 16.7 Percentage of participants |
| Nilotinb 300 mg BID | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = Interm. | 50.5 Percentage of participants |
| Nilotinb 300 mg BID | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = Low | 40.8 Percentage of participants |
| Nilotinb 300 mg BID | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = High | 41.0 Percentage of participants |
| Nilotinib 400 mg BID | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = Low | 53.4 Percentage of participants |
| Nilotinib 400 mg BID | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = High | 32.1 Percentage of participants |
| Nilotinib 400 mg BID | Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation | Sokal risk group = Interm. | 40.0 Percentage of participants |
Comparison: (Low)95% CI: [2.1, 27.5]
Comparison: (Low)95% CI: [14.6, 40.2]
Comparison: (Intermediate)95% CI: [15, 40.4]
Comparison: (Intermediate)95% CI: [4.6, 29.8]
Comparison: (High)95% CI: [10.7, 38.1]
Comparison: (High)95% CI: [2.1, 28.6]
Secondary
Actual Dose-intensity
Actual dose intensity is defined as total dose over time on treatment
Time frame: approx. 11 years
Population: Safety Set: Safety set contained 836 patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Actual Dose-intensity | 400.0 mg/day |
| Nilotinb 300 mg BID | Actual Dose-intensity | 591.1 mg/day |
| Nilotinib 400 mg BID | Actual Dose-intensity | 758.9 mg/day |
Secondary
Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts
It is defined as the time from the date of first documented BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% to the earliest of the following: Loss of BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032%, respectively, CML-related death or progression to AP/BC during study treatment. The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.
Time frame: approx. 11 years
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imatinib 400 mg QD | Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | duration of first molecular response of <=0.01% | NA Months |
| Imatinib 400 mg QD | Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | duration of first molecular response of <=0.0032% | NA Months |
| Nilotinb 300 mg BID | Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | duration of first molecular response of <=0.01% | NA Months |
| Nilotinb 300 mg BID | Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | duration of first molecular response of <=0.0032% | NA Months |
| Nilotinib 400 mg BID | Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | duration of first molecular response of <=0.01% | NA Months |
| Nilotinib 400 mg BID | Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | duration of first molecular response of <=0.0032% | NA Months |
Secondary
Duration of CCyR
Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR.
Time frame: up to 72 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Duration of CCyR | NA Months |
| Nilotinb 300 mg BID | Duration of CCyR | NA Months |
| Nilotinib 400 mg BID | Duration of CCyR | NA Months |
Secondary
Duration of MMR
Duration of MMR for patients with MMR is defined as the time between date of MMR and the earliest of the following: loss of MMR, CML-related death or progression to AP/BC during study treatment The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.
Time frame: approx. 11 years
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Duration of MMR | NA Months |
| Nilotinb 300 mg BID | Duration of MMR | NA Months |
| Nilotinib 400 mg BID | Duration of MMR | NA Months |
Secondary
Event-free Survival (EFS)
Event-free survival is defined as the time from the date of randomization to the date of first occurrence of any of the following: death due to any cause (if death is the primary reason for discontinuation), progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR
Time frame: approx. 11 years
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Event-free Survival (EFS) | NA Months |
| Nilotinb 300 mg BID | Event-free Survival (EFS) | NA Months |
| Nilotinib 400 mg BID | Event-free Survival (EFS) | NA Months |
Secondary
Overall Survival (OS)
OS is defined as the time from the date of randomization to the date death. Up to 10 calendar years of follow up from the date when the last patient randomized received the first dose of study drug in all active treatment arms of adult patients with Ph+ CML CP.
Time frame: approx. 11 years
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Overall Survival (OS) | NA Months |
| Nilotinb 300 mg BID | Overall Survival (OS) | NA Months |
| Nilotinib 400 mg BID | Overall Survival (OS) | NA Months |
Secondary
Pharmacokinetics: AUC0-last
AUC0-last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method
Time frame: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
Population: Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Pharmacokinetics: AUC0-last | 14446 h.ng/mL |
| Nilotinb 300 mg BID | Pharmacokinetics: AUC0-last | 11689 h.ng/mL |
Secondary
Pharmacokinetics: Cmax
Cmax is defined as the maximum serum concentration after dose
Time frame: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
Population: Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Pharmacokinetics: Cmax | 1555 ng/mL |
| Nilotinb 300 mg BID | Pharmacokinetics: Cmax | 1440 ng/mL |
Secondary
Pharmacokinetics: Cmin
Cmin is defined as the minimum serum concentration after dose
Time frame: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
Population: Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Pharmacokinetics: Cmin | 1430 ng/mL |
| Nilotinb 300 mg BID | Pharmacokinetics: Cmin | 915 ng/mL |
Secondary
Pharmacokinetics: Tmax
Tmax is defined as the sampling time when maximum measured serum concentration occurs
Time frame: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
Population: Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Pharmacokinetics: Tmax | 1.47 hour (h) |
| Nilotinb 300 mg BID | Pharmacokinetics: Tmax | 1.50 hour (h) |
Secondary
Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension)
This is the percentage of patients with any emergent mutation on extension treatment. The mutation comprised of T315T, less sensitive to nilotinib, unknown and sensitive to nilotinib.
Time frame: Overall for Extension study for approx. 10 years
Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension) | 20.8 Percentage of participants |
| Nilotinb 300 mg BID | Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension) | 11.5 Percentage of participants |
| Nilotinib 400 mg BID | Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension) | 33.3 Percentage of participants |
Secondary
Progression-free Survival (PFS)
Progression-free survival is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring in the core or extension study, or during the follow-up period after discontinuation of core or extension study
Time frame: approx. 11 years
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Progression-free Survival (PFS) | NA Months |
| Nilotinb 300 mg BID | Progression-free Survival (PFS) | NA Months |
| Nilotinib 400 mg BID | Progression-free Survival (PFS) | NA Months |
Secondary
Rate of ≥ 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Molecular response of \<=0.0032% is defined as BCR-ABL ratio (%) on IS \<= 0.0032% (corresponds to \>=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)
Time frame: Overall for Extension study for approx. 10 years
Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Rate of ≥ 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 35.4 Percentage of participants |
| Nilotinb 300 mg BID | Rate of ≥ 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 38.5 Percentage of participants |
| Nilotinib 400 mg BID | Rate of ≥ 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 33.3 Percentage of participants |
Secondary
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib
This is the molecular response of \<=0.0032% is defined as BCR-ABL ratio (%) on IS \<= 0.0032% (corresponds to \>=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)
Time frame: at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 12 months | 0.4 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 84 months | 19.1 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01032 at 48 months | 10.2 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 6 months | 0.0 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 72 months | 18.0 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 60 months | 19.8 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 108 months | 24.0 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 24 months | 2.8 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 120 months | 21.2 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 96 months | 23.3 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 36 months | 8.1 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 108 months | 31.9 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 6 months | 3.5 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 12 months | 4.6 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 24 months | 12.4 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 36 months | 13.8 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01032 at 48 months | 16.3 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 60 months | 32.3 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 72 months | 31.2 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 84 months | 31.6 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 96 months | 31.9 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 120 months | 27.0 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 36 months | 12.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 6 months | 1.4 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 84 months | 28.8 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 24 months | 7.8 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 120 months | 25.6 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 96 months | 32.4 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 12 months | 5.0 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 60 months | 29.5 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01032 at 48 months | 17.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 108 months | 28.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.0032% at 72 months | 28.8 Percentage of participants |
Secondary
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib
Molecular response of \<=0.01% is defined as BCR-ABL ratio (%) on IS \<= 0.01% (corresponds to \>=4 log reduction of BCR-ABL transcripts from standardized baseline value)
Time frame: at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 84 months | 29.0 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 48 months | 19.8 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 108 months | 32.2 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 72 months | 27.2 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 60 months | 31.1 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 6 months | 1.1 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 24 months | 10.2 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 12 months | 3.9 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 96 months | 28.3 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 36 months | 14.1 Percentage of participants |
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 120 months | 28.3 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 60 months | 47.9 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 6 months | 8.9 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 12 months | 12.1 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 24 months | 24.5 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 36 months | 29.4 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 48 months | 33.0 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 72 months | 44.3 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 84 months | 42.9 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 96 months | 39.7 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 108 months | 40.4 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 120 months | 35.5 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 108 months | 34.9 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 84 months | 40.6 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 24 months | 22.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 6 months | 5.7 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 96 months | 38.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 12 months | 8.9 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 60 months | 43.4 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 48 months | 29.9 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 120 months | 33.8 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 72 months | 45.2 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib | Molecular response of <=0.01% at 36 months | 23.8 Percentage of participants |
Secondary
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Molecular response of \<=0.01% is defined as BCR-ABL ratio (%) on IS \<= 0.01% (corresponds to \>=4 log reduction of BCR-ABL transcripts from standardized baseline value)
Time frame: Overall for Extension study for approx. 10 years
Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 43.8 Percentage of participants |
| Nilotinb 300 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 57.7 Percentage of participants |
| Nilotinib 400 mg BID | Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 33.3 Percentage of participants |
Secondary
Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months
CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Patients with no CCyR as the best response by any specific time point, all missing cytogenetic evaluations by that time point or Ph- at baseline are combined as Nocomplete cytogenetic response.
Time frame: 12, 24, 36, 48, 60, 72 months (M)
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg QD | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M12 | 55.5 Percentage of participants |
| Imatinib 400 mg QD | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M24 | 61.5 Percentage of participants |
| Imatinib 400 mg QD | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M36 | 14.1 Percentage of participants |
| Imatinib 400 mg QD | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M48 | 11.3 Percentage of participants |
| Imatinib 400 mg QD | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M60 | 2.5 Percentage of participants |
| Imatinib 400 mg QD | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M72 | 1.8 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M72 | 1.8 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M12 | 70.2 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M48 | 8.9 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M60 | 2.8 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M24 | 66.0 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M36 | 9.2 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M24 | 66.2 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M36 | 12.8 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M72 | 2.8 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M48 | 13.5 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M12 | 68.7 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months | CCyR at M60 | 2.8 Percentage of participants |
Secondary
Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Rate of CCyR is defined as the percentage of participants in complete cytogenetic response (CCyR). CcyR is defined as 0% of Ph+ metaphases in the bone marrow.
Time frame: Overall for Extension study for approx. 10 years
Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 72.9 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 73.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 66.7 Percentage of participants |
Secondary
Rate of Hematologic Response
Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes \< 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).
Time frame: 12 months, 24 months, Overall on Core study (approx. 11 years)
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg QD | Rate of Hematologic Response | CHR by M24 | 93.6 Percentage of participants |
| Imatinib 400 mg QD | Rate of Hematologic Response | Complete hematologic response (CHR) by M12 | 93.3 Percentage of participants |
| Imatinib 400 mg QD | Rate of Hematologic Response | CHR Overall | 94.0 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Hematologic Response | CHR by M24 | 90.8 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Hematologic Response | Complete hematologic response (CHR) by M12 | 90.1 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Hematologic Response | CHR Overall | 92.2 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Hematologic Response | Complete hematologic response (CHR) by M12 | 89.0 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Hematologic Response | CHR Overall | 90.7 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Hematologic Response | CHR by M24 | 90.4 Percentage of participants |
Secondary
Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes \< 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).
Time frame: Overall for Extension study for approx. 10 years
Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 83.3 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 84.6 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 66.7 Percentage of participants |
Secondary
Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms
MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months based on 12-month cut-off interim data.
Time frame: 12 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms | 44.3 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms | 42.7 Percentage of participants |
p-value: 0.698795% CI: [-9.8, 6.6]Cochran-Mantel-Haenszel
Secondary
Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Rate of MMR is defined as the percentage pf participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR))
Time frame: Overall for Extension study for approx. 10 years
Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 64.6 Percentage of participants |
| Nilotinb 300 mg BID | Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 73.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension) | 66.7 Percentage of participants |
Secondary
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms
MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 6 months and beyond up to 120 months based on final data.
Time frame: 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M108 | 37.5 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M72 | 41.7 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M24 | 37.5 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M6 | 12.0 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M60 | 49.1 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M36 | 38.5 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M120 | 36.4 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M96 | 37.5 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M48 | 43.8 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M12 | 22.3 Percentage of participants |
| Imatinib 400 mg QD | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M84 | 40.3 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M12 | 44.7 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M96 | 46.1 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M6 | 33.0 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M108 | 43.3 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M120 | 37.9 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M84 | 50.0 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M24 | 61.7 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M72 | 52.5 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M36 | 59.2 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M60 | 62.8 Percentage of participants |
| Nilotinb 300 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M48 | 59.9 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M120 | 39.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M60 | 61.2 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M72 | 57.7 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M6 | 29.5 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M12 | 43.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M24 | 59.1 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M36 | 57.3 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M84 | 50.9 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M96 | 46.3 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M108 | 40.2 Percentage of participants |
| Nilotinib 400 mg BID | Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms | MMR at M48 | 55.2 Percentage of participants |
Secondary
Rates of Durable MMR at 24 Months Between All 3 Arms
Durable MMR at 24 months is defined as having MMR both at 12 months and at 24 months, and with no documented loss of MMR between these 12 month and 24 month time points.
Time frame: 24 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg QD | Rates of Durable MMR at 24 Months Between All 3 Arms | 20.5 Percentage of participants |
| Nilotinb 300 mg BID | Rates of Durable MMR at 24 Months Between All 3 Arms | 41.8 Percentage of participants |
| Nilotinib 400 mg BID | Rates of Durable MMR at 24 Months Between All 3 Arms | 39.1 Percentage of participants |
95% CI: [13.9, 28.8]
95% CI: [11.3, 26]
Secondary
Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts
Time to BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% is defined as: date of first BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% - date of randomization +1.
Time frame: up to 84 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imatinib 400 mg QD | Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | time to first molecular response of <=0.01% | 30.46 Months |
| Imatinib 400 mg QD | Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | time to first molecular response of <=0.0032% | 37.29 Months |
| Nilotinb 300 mg BID | Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | time to first molecular response of <=0.01% | 19.38 Months |
| Nilotinb 300 mg BID | Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | time to first molecular response of <=0.0032% | 32.46 Months |
| Nilotinib 400 mg BID | Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | time to first molecular response of <=0.0032% | 35.94 Months |
| Nilotinib 400 mg BID | Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts | time to first molecular response of <=0.01% | 22.70 Months |
Secondary
Time to Complete Cytogenic Response (CCyR)
Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR
Time frame: 24 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Time to Complete Cytogenic Response (CCyR) | 8.5 Months |
| Nilotinb 300 mg BID | Time to Complete Cytogenic Response (CCyR) | 5.7 Months |
| Nilotinib 400 mg BID | Time to Complete Cytogenic Response (CCyR) | 5.7 Months |
Secondary
Time to First MMR
Time to MMR is defined as time from date of randomization to the date of the first documented MMR in nilotinib treatment arms, compared to imatinib in adult patients with Ph+ CML in CP.
Time frame: up to 84 months
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Time to First MMR | 14.13 Months |
| Nilotinb 300 mg BID | Time to First MMR | 8.31 Months |
| Nilotinib 400 mg BID | Time to First MMR | 8.53 Months |
Secondary
Time to Progression to AP/BC
Time to progression to AP/BC is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of CML related death.
Time frame: approx. 11 years
Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg QD | Time to Progression to AP/BC | NA Months |
| Nilotinb 300 mg BID | Time to Progression to AP/BC | NA Months |
| Nilotinib 400 mg BID | Time to Progression to AP/BC | NA Months |
Post Hoc
All Collected Deaths
On treatment deaths were collected from first patient first visit up to 28 days after study treatment discontinuation (approx. 11 years). Patients with cancer were also followed up for overall survival until the end of the trial (to collect any deaths occurring more than 28 days after study drug discontinuation). In this study, one death was collected after randomization but before the participant received study drug.
Time frame: From FPFV up to 28 days post treatment (approx. 11 years), From FPFV to LPLV (approx. 12 years)
Population: Safety analysis set consisted of all patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg QD | All Collected Deaths | On-treatment deaths | 4 deaths |
| Imatinib 400 mg QD | All Collected Deaths | Total deaths | 29 deaths |
| Nilotinb 300 mg BID | All Collected Deaths | On-treatment deaths | 10 deaths |
| Nilotinb 300 mg BID | All Collected Deaths | Total deaths | 32 deaths |
| Nilotinib 400 mg BID | All Collected Deaths | On-treatment deaths | 5 deaths |
| Nilotinib 400 mg BID | All Collected Deaths | Total deaths | 23 deaths |